Many rearrangements of carbon-carbon bonds are nucleophilic 1,2-shifts in which an electronic sextet formed on an atom (A) attached to a carbon atom induces an adjacent carbon-carbon bond to move with its electron pairs to that center to fill its valence, leaving behind a carbenium ion. The carbenium ion is then stabilized by donation of an electron pair from one of its substituents. The general mechanism for a nucleophilic 1,2-shift of a carbon-carbon bonds is illustrated in Scheme 1: ##STR1##
The above mechanism for nucleophilic 1,2-shifts of carbon-carbon bonds is of extremely broad scope and encompasses many important synthetic transformations. When A is a carbon, the reaction is a rearrangement such as the pinacol, the Wagner-Meerwein or the dienone-phenol reaction. The dienone-phenol reaction is illustrated in Scheme 2. ##STR2##
The dienone-phenol rearrangement is a acid catalyzed transformation of a 4,4-disubstitued cyclohexadienone into a 3,4-disubstituted phenol. Applied examples of the dieone-phenol rearrangement reaction are provided by R. Cassis, et al, Tetrahedron Lett. (1985), vol. 26, page 6281, by F. Hauser et al. in J. Org. Chem. (1978), vol. 431, page 113, by S. Kupchan et al. in Heterocycles (1976), vol. 4, page 235, by U. Eder et al. in Chem. Ber. (1978), vol. 111, page 939, and by D. Hart et al. in Tetrahedron (1992), vol. 48, page 8179. The acid catalyzed mechanism for the dienone-phenol rearrangement reaction for compound 7 is illustrated in FIG. 2. In the case of compound 7, the benzyl group migrates preferentially to give phenol 8. The reaction mechanism involves pre-equilibrium protonation of the carbonyl by the acid catalyst to form intermediate 10, followed by a rate determining migration of the benzyl group to form intermediate 12. Proton abstraction from position C(3) finally leads to aromatization and regeneration of the acid catalyst.
Cyclohexadienones are members of a class of molecules known as blocked aromatic molecules. Blocked aromatic molecules are molecules having a six membered carbon ring, five of the six ring carbons being conjugated by means of linear or cross-conjugation, one of the five conjugated ring carbons including a reducible substituent, and the remaining sixth unconjugated ring carbon including disubstitutions with at least one substituent being susceptible to a sigmatropic shift, i.e., a migrating substituent. Blocked aromatic molecules can undergo aromatization by means of skeletal rearrangements involving 1,2-, 1,3-, 1,4-, 1,5-, 3,3-, 3,4-, 3,5-, or 5,5- sigmatropic shifts. Representative members of the class of blocked aromatic molecules include disubstituted cyclohexadienones, methylene-cyclohexadienes (semibenzenes), and cyclohexadienyl carbenes, illustrated in Scheme 3 below: ##STR3##
Amongst the various class members indicated above, cyclohexadienones are generally the least susceptible to skeletal rearrangements. The driving force for aromatizing cyclohexadienones is tempered by the greater relative stability of their carbonyl structures over their corresponding enol structures. As a rule, however, all blocked aromatic molecules more readily undergo skeletal rearrangements to achieve aromatization as compared to corresponding acyclic analogs because the transition states of blocked aromatic molecules attain a higher degree of aromatic character.
Cyclohexadienones may undergo thermal (spontaneous) or acid-catalyzed rearrangements. Acid catalyzed rearrangements of 4,4-disubstituted cyclohexadienones (para cyclohexadienones) involve a three step reaction mechanism, illustrated in FIG. 2. Initially, the carbonyl group of the 4,4-disubstituted cyclohexadienone undergoes a protonation by the acid catalyst resulting in a partial transfer of charge to the conjugated ring carbons. The protonation of the carbonyl group is then followed by a rate determining 1,2- shift of a substituent from the C(4) ring position to the C(3) ring position via a transition state. The transition state includes a three membered ring involving the migrating substituent, the C(3) ring carbon and the C(4) ring carbon. The transition state is stabilized by a partial localization of charge onto this three membered ring. After completion of the 1,2- shift, aromatization is completed by abstraction of the proton from the C(3) ring position and regeneration of the acid catalyst. The reaction mechanism of corresponding thermal or spontaneous rearrangements do not include an intermediate in which the carbonyl group is protonated.
There are several species of migrating substituents disclosed in the prior art, e.g., benzyl substituents, allyl substituents, and alkyl substituents. All three species have been shown to participate as migrating groups within dienone-phenol rearrangement reactions and are reviewed by B. Miller in Account. Chem. Res. (1975) vol. 8, pages 245-256. Benzyl substituents are generally observed to more readily undergo a 1,2- shift in a dienone-phenol rearrangement reaction. Allyl groups are highly migratory and can undergo a 1,2- shift in a dienone-phenol rearrangement reaction but are also known to undergo 3,3- shifts. Alkyl substituents are generally slower migrators than allyl or benzyl substituents.
Although rearrangement reactions involving cyclohexadienones are chemically important, many migrating species are slow and thereby limit their applicability. Energy barriers for sigmatropic shifts can be relatively high. What is needed is a stereospecific method for catalyzing cyclohexadienone rearrangements.
It is known that catalytic antibodies can be generated by inoculating an immune responsive animal with a stable transition state analog of the chemical reaction sought to be catalyzed. This technique provides a rapid and practical entry into new protein catalysts and has been successfully applied to a number of chemical tranformations, e.g., R. A. Lerner et al., Science (1991), vol. 252, pages 659-667 and P. G. Schultz et al., Acc. Chem. Res. (1993), vol. 26, page 391. However, only a few reactions involving carbon-carbon bonds have been catalyzed by antibodies. Such reactions have been reviewed by D. Hilvert in Acc. Chem. Res. (1993), vol. 26, page 552. Generation of catalytic antibody for catalyzing the Diels-Alder reaction is disclosed by D. Hilvert et al. in J. Am. Chem. Soc. (1989), vol. 111, page 9261, by A. C. Braisted et al. in J. Am. Chem. Soc. (1990), vol. 112, page 7430, and by V. Grouverneur et al. in Science (1993), vol. 262, page 204. Generation of catalytic antibody for catalyzing the Cope rearrangement reaction is disclosed by D. Hilvert et al. in J. Am. Chem. Soc. (1988), vol. 110, page 5593, by B. Jackson et al. in J. Am. Chem. Soc. (1988), vol. 110, page 4841, and by D. Jackson et al. in Angew. Chemie Int. Ed. Engl. (1992 ), vol. 31, page 182. Generation of catalytic antibody for catalyzing decarboxylation reactions is disclosed by C. Lewis et al. in Science (1991), vol. 253, page 1019, by J. A. Ashley, et al. in J. Am. Chem. Soc. (1993), vol. 115, page 2515. However, no one has reported the generation of a catalytic antibody for catalyzing nucleophilic 1, 2-shifts of carbon-carbon bonds in general or of the dienone-phenol rearrangement reaction in particular.